Hippo Pathway in Regulating Drug Resistance of Glioblastoma

Glioblastoma (GBM) represents the most common and malignant tumor of the Central Nervous System (CNS), affecting both children and adults. GBM is one of the deadliest tumor types and it shows a strong multidrug resistance (MDR) and an immunosuppressive microenvironment which remain a great challenge to therapy. Due to the high recurrence of GBM after treatment, the understanding of the chemoresistance phenomenon and how to stimulate the antitumor immune response in this pathology is crucial. The deregulation of the Hippo pathway is involved in tumor genesis, chemoresistance and immunosuppressive nature of GBM. This pathway is an evolutionarily conserved signaling pathway with a kinase cascade core, which controls the translocation of YAP (Yes-Associated Protein)/TAZ (Transcriptional Co-activator with PDZ-binding Motif) into the nucleus, leading to regulation of organ size and growth. With this review, we want to highlight how chemoresistance and tumor immunosuppression work in GBM and how the Hippo pathway has a key role in them. We linger on the role of the Hippo pathway evaluating the effect of its de-regulation among different human cancers. Moreover, we consider how different pathways are cross-linked with the Hippo signaling in GBM genesis and the hypothetical mechanisms responsible for the Hippo pathway activation in GBM. Furthermore, we describe various drugs targeting the Hippo pathway. In conclusion, all the evidence described largely support a strong involvement of the Hippo pathway in gliomas progression, in the activation of chemoresistance mechanisms and in the development of an immunosuppressive microenvironment. Therefore, this pathway is a promising target for the treatment of high grade gliomas and in particular of GBM.

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Hepatic Hippo signaling inhibits development of hepatocellular carcinoma

Clinical and Molecular Hepatology ◽

10.3350/cmh.2020.0178 ◽

2020 ◽

Vol 26 (4) ◽

pp. 742-750

Author(s):

Yuchen Liu ◽

Xiaohui Wang ◽

Yingzi Yang

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Cancer ◽

Primary Liver Cancer ◽

Hippo Pathway ◽

Hepatocyte Proliferation ◽

Binding Motif ◽

Hippo Signaling ◽

Human Liver Cancer ◽

Kinase Cascade ◽

The Hippo Pathway

Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.

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Hippo signaling in the kidney: the good and the bad

AJP Renal Physiology ◽

10.1152/ajprenal.00500.2015 ◽

2016 ◽

Vol 311 (2) ◽

pp. F241-F248 ◽

Cited By ~ 14

Author(s):

Jenny S. Wong ◽

Kristin Meliambro ◽

Justina Ray ◽

Kirk N. Campbell

Keyword(s):

Embryonic Development ◽

Current Knowledge ◽

Hippo Pathway ◽

Hippo Signaling ◽

Filtration Barrier ◽

Signaling Axis ◽

Kinase Cascade ◽

Barrier Regulation ◽

Renal Tubular ◽

The Hippo Pathway

The Hippo signaling pathway is an evolutionarily conserved kinase cascade, playing multiple roles in embryonic development that controls organ size, cell proliferation, and apoptosis. At the center of this network lie the Hippo kinase target and downstream pathway effector Yes-associated protein (YAP) and its paralog TAZ. In its phosphorylated form, cytoplasmic YAP is sequestered in an inactive state. When it is dephosphorylated, YAP, a potent oncogene, is activated and relocates to the nucleus to interact with a number of transcription factors and signaling regulators that promote cell growth, differentiation, and survival. The identification of YAP activation in human cancers has made it an attractive target for chemotherapeutic drug development. Little is known to date about the function of the Hippo pathway in the kidney, but that is rapidly changing. Recent studies have shed light on the role of Hippo-YAP signaling in glomerular and lower urinary tract embryonic development, maintenance of podocyte homeostasis, the integrity of the glomerular filtration barrier, regulation of renal tubular cyst growth, renal epithelial injury in diabetes, and renal fibrogenesis. This review summarizes the current knowledge of the Hippo-YAP signaling axis in the kidney under normal and disease conditions.

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Hippo and rassf1a Pathways: A Growing Affair

Molecular Biology International ◽

10.1155/2012/307628 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 14

Author(s):

Francesca Fausti ◽

Silvia Di Agostino ◽

Andrea Sacconi ◽

Sabrina Strano ◽

Giovanni Blandino

Keyword(s):

Developmental Biology ◽

Tissue Regeneration ◽

Target Genes ◽

Hippo Pathway ◽

Hippo Signaling ◽

Transcriptional Coactivator ◽

Pathway Activity ◽

Kinase Cascade ◽

The Hippo Pathway ◽

The Impact

First discovered in Drosophila, the Hippo pathway regulates the size and shape of organ development. Its discovery and study have helped to address longstanding questions in developmental biology. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the Yki protein (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation, survival, and apoptosis. A dysfunction of the Hippo pathway activity is frequently detected in human cancers. Recent studies have highlighted that the Hippo pathway may play an important role in tissue homoeostasis through the regulation of stem cells, cell differentiation, and tissue regeneration. Recently, the impact of RASSF proteins on Hippo signaling potentiating its proapoptotic activity has been addressed, thus, providing further evidence for Hippo's key role in mammalian tumorigenesis as well as other important diseases.

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Yorkie-independent negative feedback couples Hippo pathway activation with Kibra degradation

10.1101/2020.07.08.192765 ◽

2020 ◽

Author(s):

Sherzod A. Tokamov ◽

Ting Su ◽

Anne Ullyot ◽

Richard G. Fehon

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Hippo Pathway ◽

Tissue Growth ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

The Core ◽

Pathway Activation ◽

The Hippo Pathway ◽

Transcriptional Output

AbstractThe Hippo signaling pathway regulates tissue growth in many animals. Multiple upstream components are known to promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Kibra levels independently of Yorkie-mediated transcriptional output. We find that the Hippo pathway promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires the core kinases Hippo and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators including Crumbs and Expanded. Moreover, Kibra degradation appears patterned across tissue. We propose that Kibra degradation by the Hippo pathway serves as a negative feedback loop to tightly control Kibra-mediated Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

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SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽

10.7554/elife.30278 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 42

Author(s):

Sung Jun Bae ◽

Lisheng Ni ◽

Adam Osinski ◽

Diana R Tomchick ◽

Chad A Brautigam ◽

...

Keyword(s):

Molecular Mechanisms ◽

Hippo Pathway ◽

Tissue Growth ◽

Activation Loop ◽

Hippo Signaling ◽

Ww Domains ◽

Kinase Activation ◽

Genetic Ablation ◽

Kinase Cascade ◽

The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

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Regulation and functions of the Hippo pathway in stemness and differentiation

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa048 ◽

2020 ◽

Vol 52 (7) ◽

pp. 736-748 ◽

Cited By ~ 1

Author(s):

Xiaolei Cao ◽

Chenliang Wang ◽

Jiyang Liu ◽

Bin Zhao

Keyword(s):

Cell Proliferation ◽

Tissue Regeneration ◽

Hippo Pathway ◽

Binding Motif ◽

Cell Fates ◽

Self Renewal ◽

Proliferation And Apoptosis ◽

Kinase Cascade ◽

The Hippo Pathway

Abstract The Hippo pathway plays important roles in organ development, tissue regeneration, and human diseases, such as cancer. In the canonical Hippo pathway, the MST1/2-LATS1/2 kinase cascade phosphorylates and inhibits transcription coactivators Yes-associated protein and transcription coactivator with PDZ-binding motif and thus regulates transcription of genes important for cell proliferation and apoptosis. However, recent studies have depicted a much more complicate picture of the Hippo pathway with many new components and regulatory stimuli involving both chemical and mechanical signals. Furthermore, accumulating evidence indicates that the Hippo pathway also plays important roles in the determination of cell fates, such as self-renewal and differentiation. Here, we review regulations of the Hippo pathway and its functions in stemness and differentiation emphasizing recent discoveries.

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The Hippo pathway component Wwc2 is a key regulator of embryonic development and angiogenesis in mice

Cell Death and Disease ◽

10.1038/s41419-021-03409-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anke Hermann ◽

Guangming Wu ◽

Pavel I. Nedvetsky ◽

Viktoria C. Brücher ◽

Charlotte Egbring ◽

...

Keyword(s):

Embryonic Development ◽

Cell Fate ◽

Target Genes ◽

Hippo Pathway ◽

Growth Control ◽

Binding Motif ◽

Hippo Signaling ◽

Large Tumor ◽

Organ Growth ◽

The Hippo Pathway

AbstractThe WW-and-C2-domain-containing (WWC) protein family is involved in the regulation of cell differentiation, cell proliferation, and organ growth control. As upstream components of the Hippo signaling pathway, WWC proteins activate the Large tumor suppressor (LATS) kinase that in turn phosphorylates Yes-associated protein (YAP) and its paralog Transcriptional coactivator-with-PDZ-binding motif (TAZ) preventing their nuclear import and transcriptional activity. Inhibition of WWC expression leads to downregulation of the Hippo pathway, increased expression of YAP/TAZ target genes and enhanced organ growth. In mice, a ubiquitous Wwc1 knockout (KO) induces a mild neurological phenotype with no impact on embryogenesis or organ growth. In contrast, we could show here that ubiquitous deletion of Wwc2 in mice leads to early embryonic lethality. Wwc2 KO embryos display growth retardation, a disturbed placenta development, impaired vascularization, and finally embryonic death. A whole-transcriptome analysis of embryos lacking Wwc2 revealed a massive deregulation of gene expression with impact on cell fate determination, cell metabolism, and angiogenesis. Consequently, a perinatal, endothelial-specific Wwc2 KO in mice led to disturbed vessel formation and vascular hypersprouting in the retina. In summary, our data elucidate a novel role for Wwc2 as a key regulator in early embryonic development and sprouting angiogenesis in mice.

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Hippo Signaling Pathway as a New Potential Target in Non-Melanoma Skin Cancers: A Narrative Review

Life ◽

10.3390/life11070680 ◽

2021 ◽

Vol 11 (7) ◽

pp. 680

Author(s):

Igor Aleksander Bednarski ◽

Magdalena Ciążyńska ◽

Karolina Wódz ◽

Izabela Dróżdż ◽

Małgorzata Skibińska ◽

...

Keyword(s):

Cell Carcinoma ◽

Hippo Pathway ◽

Short Review ◽

Tissue Growth ◽

Hippo Signaling ◽

Skin Cancers ◽

Promising Target ◽

Important Regulator ◽

The Hippo Pathway ◽

Melanoma Skin

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most frequently diagnosed cancers in humans, however, their exact pathogenesis is not fully understood. In recent years, it has been hypothesized that the recently discovered Hippo pathway could play a detrimental role in cutaneous carcinogenesis, but no direct connections have been made. The Hippo pathway and its effector, YAP, are responsible for tissue growth by accelerating cell proliferation, however, YAP upregulation and overexpression have also been reported in numerous types of tumors. There is also evidence that disrupted YAP/Hippo signaling is responsible for cancer growth, invasion, and metastasis. In this short review, we will explore whether the Hippo pathway is an important regulator of skin carcinogenesis and if it could be a promising target for future therapies.

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Activation mechanisms of the Hippo kinase signaling cascade

Bioscience Reports ◽

10.1042/bsr20171469 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 20

Author(s):

Sung Jun Bae ◽

Xuelian Luo

Keyword(s):

Hippo Pathway ◽

Adaptor Proteins ◽

Tissue Growth ◽

Fine Tuning ◽

Hippo Signaling ◽

Kinase Activation ◽

The Core ◽

Activation Mechanisms ◽

Kinase Cascade ◽

The Hippo Pathway

First discovered two decades ago through genetic screens in Drosophila, the Hippo pathway has been shown to be conserved in metazoans and controls organ size and tissue homeostasis through regulating the balance between cell proliferation and apoptosis. Dysregulation of the Hippo pathway leads to aberrant tissue growth and tumorigenesis. Extensive studies in Drosophila and mammals have identified the core components of Hippo signaling, which form a central kinase cascade to ultimately control gene expression. Here, we review recent structural, biochemical, and cellular studies that have revealed intricate phosphorylation-dependent mechanisms in regulating the formation and activation of the core kinase complex in the Hippo pathway. These studies have established the dimerization-mediated activation of the Hippo kinase (mammalian Ste20-like 1 and 2 (MST1/2) in mammals), the dynamic scaffolding and allosteric roles of adaptor proteins in downstream kinase activation, and the importance of multisite linker autophosphorylation by Hippo and MST1/2 in fine-tuning the signaling strength and robustness of the Hippo pathway. We highlight the gaps in our knowledge in this field that will require further mechanistic studies.

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STK25 suppresses Hippo signaling by regulating SAV1-STRIPAK antagonism

eLife ◽

10.7554/elife.54863 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Sung Jun Bae ◽

Lisheng Ni ◽

Xuelian Luo

Keyword(s):

Hippo Pathway ◽

Human Cells ◽

Tissue Homeostasis ◽

Organ Size ◽

Scaffolding Protein ◽

Hippo Signaling ◽

Mutual Antagonism ◽

Kinase Cascade ◽

The Hippo Pathway

The MST-LATS kinase cascade is central to the Hippo pathway that controls tissue homeostasis, development, and organ size. The PP2A complex STRIPAKSLMAP blocks MST1/2 activation. The GCKIII family kinases associate with STRIPAK, but the functions of these phosphatase-associated kinases remain elusive. We previously showed that the scaffolding protein SAV1 promotes Hippo signaling by counteracting STRIPAK (Bae et al., 2017). Here, we show that the GCKIII kinase STK25 promotes STRIPAK-mediated inhibition of MST2 in human cells. Depletion of STK25 enhances MST2 activation without affecting the integrity of STRIPAKSLMAP. STK25 directly phosphorylates SAV1 and diminishes the ability of SAV1 to inhibit STRIPAK. Thus, STK25 as the kinase component of STRIPAK can inhibit the function of the STRIPAK inhibitor SAV1. This mutual antagonism between STRIPAK and SAV1 controls the initiation of Hippo signaling.

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